The Rogel Cancer Center at the University of Michigan led research and found that the major chemotherapy drug that is given to patients of pancreatic cancer is not as effective because it releases similar compounds like the ones released by immune cells that are tumor-associated.
Gemcitabine, a chemotherapy drug, is basically an anti-metabolite. It resembles regular metabolites that are consumed by the cell, however, once they are inside the cell, they kill it by its functions.
“Why does gemcitabine work pretty well in some cancers but not in pancreatic cancer, that’s the big question my lab was trying to answer,” said the senior author of the study, Dr. Costas Lyssiotis.
“Malignant cells often only make up about 10 percent of a tumor,” said the first author of the study, Dr. Christopher J. Halbrook. “The remaining 90 percent are other types of cells that support the growth of that tumor — like structural cells, vasculature, and immune cells. Our work has been focused on the interaction between malignant cells and immune cells.”
Lyssiotis and his team examined the interaction of malignant cells and the macrophages associated to tumors and found that the immune cells were releasing a swarm of compounds called pyrimidines, that are metabolized by cells that are malignant.
One of the pyrimidines, deoxycytidine, possesses a chemical structure that resembles gemcitabine and also blocks the activity of the chemotherapy drug in malignant cells.
“Deoxycytidine basically outcompetes gemcitabine,” said Lyssiotis.
After pharmacologically and genetically reducing the no. of macrophages that are associated with tumors in the models of the mouse, the research team proved that the tumors resisted lesser to gemcitabine.
“When we think of personalized medicine, we often think about what’s going inside of the malignant cells, what specific genetic mutations a patient’s tumor may have,” said Lyssiotis. “In our case, we’re thinking about, ‘What does this tumor look like as a whole? What does its ecosystem of cells look like?’ And hopefully we can use an understanding of the interaction between different types of cells to develop new approaches to treatment.”